Several TRP channels have been shown to be directly gated by thermal stimuli. TRPV1, the first temperature-activated TRP identified, responds to noxious heat (42C) and to capsaicin and is specifically expressed in a subset of nociceptive (pain sensing) neurons in the dorsal root ganglia (DRG). TRPM8, expressed in a separate population of neurons in the DRG, responds to cool temperatures (25C) and to menthol. Their distinct sensory modalities and expression patterns suggest that TRPV1 and TRPM8 transmit "hot" and "cool" signals via different pathways. Recently I identified ANKTM1, a TRP-like channel that responds to noxious cold temperatures (17C) and is expressed in a subset of nociceptive neurons that also express TRPV1. I also identified DRG neurons in culture that respond to both noxious heat and cold, but not to menthol, suggesting neurons that transmit a cool/pleasant signal are separate from those that convey both noxious heat and cold. I therefore propose that together TRPV1 and ANKTM1 mark "polymodal nociceptors," neurons that transmit several painful modalities. The central hypothesis of this proposal is that ANKTM1 activation in sensory neurons elicits a painful signal in vivo. This hypothesis is based on preliminary data that Methyl Salicylate, a specific activator of ANKTM1, causes nociceptive behaviors in mice. The broad objective of this proposal is to examine the consequences of ANKTM1 activation by using Methyl Salicylate as a sensory readout. The aims of the proposal apply RNAi in cultured neurons and behavioral assays and gene knockout in mice. These studies will further elucidate the role of ANKTM1 in temperature and pain detection. [unreadable] [unreadable]